Glioblastoma (GBM, the acronym is derived from the previous name Glioblastoma Multiforme) is the most common adult malignant brain tumor (Central Brain Tumor Registry of the United States, 2012). GBM accounts for 80% of all primary malignant brain tumors diagnosed in the United States and 30% of all brain tumors, with only meningiomas being more frequently reported. GBM has the worst prognosis of any of the malignant brain tumors tracked by the Central Brain Tumor Registry of the United States, with three year survival rates below 10%. The majority of patients survive less than one year after diagnosis.
Glioblastomas are currently treated with surgical resection when possible, depending upon the location of the tumor. Surgery is typically followed by adjuvant radiation therapy (Walker and Green, 1980) and treatment with the chemotherapeutic DNA alkylating agent temozolomide (Athanassiou et al., 2005; Stupp et al., 2005, 2009). Despite these measures, a report showed that in patients receiving adjuvant therapy the median time to progression was only 6.9 months (Stupp et al., 2005).
Because of the failure of more traditional therapies, very poor patient outcomes, and previous studies that had noted heterogeneity among glioblastomas (Liang et al., 2005; Maher et al., 2006; Mischel et al., 2003; Phillips et al., 2006), the Cancer Genome Atlas (TCGA) published a genetic analysis of a set of over 200 glioblastomas (The Cancer Genome Atlas, 2008). This analysis revealed that a few core pathways are altered in a large majority of tumors including the phosphoinositide 3-kinase (also referred to as “PI3 kinase” or “PI3K”) cell signaling pathway. Similarly, TCGA analysis found that 72% of all glioblastomas have a mutation or amplification in at least one receptor tyrosine kinase (RTK). There are three RTKs which are commonly altered in glioma: Epidermal Growth Factor Receptor (EGFR), MET, and Platelet Derived Growth Factor Receptor alpha (PDGFRα).
PDGFRs and their ligands have been shown to have a role in tumorigenesis in several cancers, including gliomas (Andrae et al., 2008). TCGA analysis of gliomas revealed that 16% of tumors had mutations or amplifications in PDGFRA, and 3% had amplifications in the ligand PDGFA (Cerami et al., 2012; Gao et al., 2013). The PDGFR mutations noted in the TCGA analysis are primarily in the extracellular domain of the protein.
To date there have been a number of clinical trials of EGFR or PI3K/mTOR pathway inhibitors. However, none have resulted in a durable response longer than a few weeks or a durable response in more than 5% of patients (Mellinghoff and Schultz, 2012).
Thus, there is a need for the development of better strategies for the treatment of glioma, including customized patient-specific approaches that take into account the different mutations present in the tumors of different patients.